1. Field of the Invention
The present invention relates to a series of substituted tetracyclic heteroaromatic benzofuranoindoles and indenoindoles having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation. Such disorders include, but are limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
2. Description of the Prior Art
Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews [Rudy, B. Neuroscience 1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12, 569-591; Gopalakrishnan, M. et al., Drug Development Research 1993, 28 95-127; Primeau, J. et al. Current Pharmaceutical Design 1995, 1, 391-406; Edwards, G. et al. Exp. Opin. Invest. Drugs 1996, 5 (11), 1453-1464]. Activation of these channels augments transmembrane K+ flux, thus effecting hyperpolarization of the cell membrane towards the Nernst K+ equilibrium potential (xe2x88x9290 mV), and subsequent closure of the voltage-gated Ca2+ channels. As a result, the hyperactive cell becomes less excitable and therefore less prone to further stimulation; thus leading to relaxation in the case of smooth muscle. As a result of this pharmacologic action, therapeutic potential for potassium channel activators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of heterotetracyclic methylamino benzofuranindoles compounds are reported by Bair, K. W., in WO 91/14688 and EP-44703-A1 and are useful as antitumor and biocidal agents. 
An example disclosed is 2-methyl-2-(((10-methyl-10H-benzofuro(3,2-b)indol-6-yl)methyl)amino)-1,3-propanediol.
A series of indenoindoles claimed as useful medicinal antioxidants and free-radical scavengers are disclosed by Sainsbury et al. in EP-404536-A1. 
A series of indenoindoles useful as a component in an organic electroluminescent element are disclosed in JP-06-228554. 
A related series of tetrahydro indeno-indole analogs is disclosed by Sainsbury, M. in WO 90/15799 and in EP-409410-B1. 
These compounds are also claimed as useful antioxidants for the treatment of atherosclerosis, thrombosis, embolism and Parkinson""disease.
The synthesis and antioxidant properties of a series of indeno-indoles and indolines are reported in several papers [Brown, D. W. et al., Tetrahedron 1991, 47 (25), 4383-4408; Brown, D. W., Tetrahedron 1993, 49 (39), 8919-8932; Graupner, P. R. et al., Tetrahedron Lett. 1995, 36 (32) 5827-5830; Shertzer, H. G. et al., Fd. Chem. Tox. 1991, 29 (6) 391-400]. Reported also by Brown, F. C. et al., Tetrahedron Lett. 1991, 32 (6) 801-802 are flash-vacuum pyrolysis methods for the synthesis of substituted indeno[1,2-b]indoles.
The present invention differs from the prior art by requiring the Z substituent, defined below as a carboxylic acid moiety, a bioisosteric equivalent of a carboxylic acid, or a derivative thereof to be substituted at position a of the tetracyclic heteroaromatic benzofuranoindoles and indenoindoles of Formulae (I) and (II). The compounds of this invention have reported potassium channel activation and the resulting smooth muscle relaxing properties are uniquely tissue-selective for bladder tissue.
Accordingly, the present invention discloses compounds represented by Formula (I): 
wherein:
R1, R2 and R3 are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, xe2x80x94SO3H, xe2x80x94SO2NH2, xe2x80x94NHSO2R14, 
R15SO2xe2x80x94, carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
Y is xe2x80x94Oxe2x80x94 and xe2x80x94NR4;
X is xe2x80x94Oxe2x80x94, when Y is xe2x80x94NR4;
X is xe2x80x94NR4, when Y is xe2x80x94Oxe2x80x94;
R4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms;
R5 and R6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine;
Z substituted at position a is selected from the group consisting of 
M is an alkali metal cation or an alkaline earth metal cation;
R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R8 and R9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R10, R11, R12 and R13 are independently, alkyl of 1 to 10 carbon atoms; R14 is a straight chain alkyl of 1 to 10 carbon atoms; R15 is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
provided that R1, R2 and R3 are not hydrogen when Z is xe2x80x94CHO, Y is xe2x80x94Oxe2x80x94 and X is xe2x80x94Nxe2x80x94CH3;
or a pharmaceutically acceptable salt thereof.
A preferred aspect of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroup below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a) Y is xe2x80x94NR4 when X is xe2x80x94Oxe2x80x94;
More preferred aspects of this invention includes compounds of Formula (I) including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
Z is xe2x80x94CO2H;
R1 is halogen or nitro;
a) X is xe2x80x94Oxe2x80x94, when Y is xe2x80x94NR4; and
b) X is xe2x80x94NR4, when Y is xe2x80x94Oxe2x80x94;
Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or a pharmaceutically acceptable salt thereof:
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid hydroxy-methyl amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbaldehyde;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbonitrile hydrate;
8-Bromo-1-(1H-tetrazol-5-yl)-10H-benzo[4,5]furo[3,2-b]indole;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,2,2-trimethyl-propyl)-amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,1-dimethyl-propyl)-amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methylamide;
8-Bromo-10-methyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester; and
10H-Benzo[4,5]furo[3,2-b]indole-1-carboxylic acid.
In particular, this invention also provides a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals preferably mammals, most preferably humans an effective amount of a compound of general Formula (II) or a pharmaceutically acceptable salt thereof: 
wherein:
R1, R2 and R3 are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms (optionally substituted with halogen), amino, alkylamino of 1 to 10 carbon atoms, xe2x80x94SO3H, xe2x80x94SO2NH2, xe2x80x94NHSO2R14, 
R15SO2xe2x80x94, carboxyl and aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
Y is xe2x80x94NR4 and xe2x80x94CR5R6;
X is xe2x80x94Oxe2x80x94, when Y is xe2x80x94NR4;
X is xe2x80x94NR4, when Y is xe2x80x94CR5R6;
X is xe2x80x94CR5R6, when Y is xe2x80x94NR4;
R4 is hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or an acyl substituent selected from formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms and arylalkylsulfonyl of 7 to 12 carbon atoms;
R5 and R6 are independently hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 6 to 12 carbon atoms, or fluorine;
Z substituted at position a is selected from the group consisting of 
M is an alkali metal cation or an alkaline earth metal cation;
R7 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R8 and R9 are, independently, hydrogen, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, or aryl of 6 to 12 carbon atoms;
R10, R11, R12 and R13 are independently, alkyl of 1 to 10 carbon atoms; R14 is a straight chain alkyl of 1 to 10 carbon atoms; R15 is a straight chain alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
or a pharmaceutically acceptable salt thereof.
A preferred aspect of this invention includes compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are those in the subgroups below, wherein the other variables of Formula (II) in the subgroups are as defined above wherein:
a) X is xe2x80x94Oxe2x80x94, when Y is xe2x80x94NR4;
b) X is xe2x80x94NR4, when Y is xe2x80x94CR5R6; and
c) X is xe2x80x94CR5R6, when Y is xe2x80x94NR4.
More preferred aspects of this invention includes compounds of Formula (II) including pharmaceutically acceptable salts thereof for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are those in the subgroups below, wherein the other variables of Formula (II) in the subgroups are as defined above wherein:
Z is xe2x80x94CO2H;
R1 is halogen or nitro;
a) X is xe2x80x94Oxe2x80x94, when Y is xe2x80x94NR4;
b) X is xe2x80x94NR4, when Y is xe2x80x94CR5R6; and
c) X is xe2x80x94CR5R6, when Y is xe2x80x94NR4.
Specifically preferred compounds of this invention according to general Formula (II) for use as a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals preferably mammals, most preferably humans in need thereof are the following compounds or a pharmaceutically acceptable salt thereof:
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Iodo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Chloro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Nitro-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid dihydrate;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester;
(8-Bromo-10H-benzo[4,5]furo[3,2-b]indol-1-yl)-methanol;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid hydroxy-methyl amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbaldehyde;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carbonitrile hydrate;
8-Bromo-1-(1H-tetrazol-5-yl)-10H-benzo[4,5]furo[3,2-b]indole;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,2,2-trimethyl-propyl)-amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (1,1-dimethyl-propyl)-amide;
8-Bromo-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methylamide;
8-Bromo-10-methyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid methyl ester;
10H-Benzo[4,5]furo[3,2-b]indole-1-carboxylic acid;
8-Iodo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid 0.6 hydrate;
8-Sulfamoyl-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid hemihydrate;
8-Fluoro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;
8-Chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;
8-Trifluoromethoxy-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid;
8-Chloro-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid ethyl ester;
8-Bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid ethyl ester;
10,10-Dimethyl-3-nitro-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid;
8-Bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid; and
3-Bromo-5,10-dihydro-indeno[1,2-b]indole-6-carboxylic acid.
It is understood that the definition of compounds of Formulae (I) and (II), when R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 or R15 contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, the definition encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formulae (I) and (II). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R1, R2, R3, R4, R5, R6, R7, R8, or R9 contains a carboxyl group, or in the cases where Z is a carboxylic acid, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
For the compounds of Formulae (I) and (II) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Cycloalkyl as used herein means a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Aryl as used herein means a homocyclic aromatic radical, whether or not fused, having 6 to 12 carbon atoms. Preferred aryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkyl amino of 1 to 10 carbon atoms.
Aroyl as used herein refers to xe2x80x94C(O)aryl where aryl is as previously defined. Examples include benzoyl and naphthoyl which may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3 and phenyl.
Aralkyl as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined. Exemplary aralkyl groups include benzyl and phenethyl.
Alkenyl as used herein means a branched or straight chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon double bond. Alkenyl, may be used synonymously with the term olefin and includes alkylidenes. Exemplary alkenyl groups include ethylene, propylene and isobutylene.
Alkanoyl as used herein refers to xe2x80x94C(O)alkyl where alkyl is as previously defined.
Alkenoyl as used herein refers to xe2x80x94C(O)alkenyl where alkenyl as previously defined.
Alkoxy as used herein means an xe2x80x94O-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Arylalkanoyl as used herein refers to a carbonyl group or radical directly bonded to an alkyl group of 1 to 10 carbon atoms which is terminally substituted by an aryl group as previously defined, for example phenylacetic acid. The aryl group may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and xe2x80x94CF3.
Arylalkenoyl as used herein refers to a carbonyl group or radical directly bonded to an alkenyl group of 2 to 12 carbon atoms which is terminally substituted by an aryl group as previously defined. The aryl group may optionally be substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and xe2x80x94CF3.
Alkylsulfonyl as used herein refers to the radical xe2x80x94SO2alkyl where alkyl is as previously defined.
Arylsulfonyl as used herein refers to the radical xe2x80x94SO2aryl where aryl is as previously defined.
Arylalkylsulfonyl as used herein refers to the radical arylalkylO2Sxe2x80x94 where arylalkyl is as previously defined.
Phenyl as used herein refers to a 6-membered aromatic ring.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above.
The range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
The present invention also provides a process for the preparation of compounds of Formulae (I) and (II). Compounds of Formulae (I) and (II) wherein X is xe2x80x94Oxe2x80x94 and Y is xe2x80x94NR4, where R4 is as defined above, may be prepared as shown in Scheme 1. Treatment of an appropriately substituted benzofuranone 1 where R1, R2 and R3 are hereinbefore defined with 2-hydrazinobenzoic acid 2 in aqueous media affords the corresponding phenyl hydrazone 3. This intermediate is either isolated and purified and then converted, or subjected crude to a microwave-facilitated Fischer-indole cyclization in an acidic media such as, but not limited to, formic acid to yield the substituted benzo[4,5]furo[3,2-b]indole 4. Standard procedures may then be utilized to introduce R4 when R4 is not a hydrogen atom to prepare carboxylic acid 5. 
Alternatively, for examples represented by Formulae (I) and (II) wherein X is xe2x80x94NR4, and Y is xe2x80x94CR5R6, where R4, R5 and R6 are as defined above, may be prepared as shown in Scheme II. An appropriately substituted phenylhydrazine (6) where R1, R2 and R3 are hereinbefore defined may be treated with an indanone-1-carboxylic acid (7) where R5 and R6 are hereinbefore defined to afford phenyl hydrazone (8) which is further reacted in the presence of an acid, such as, but not limited to, formic acid in a microwave-facilitated Fischer-indole cyclization to yield indeno[1,2-b]indole 9. 
Standard procedures may then be utilized to introduce R4 when R4 is not a hydrogen atom to give carboxylic acid 10.
Compounds of Formulae (I) and (II) wherein X is xe2x80x94CR5R6, and Y is xe2x80x94NR4, where R4, R5 and R6 are as defined above, may be prepared as shown in Scheme III. An appropriately substituted indanone (11) where R1, R2, R3, R5 and R6 are hereinbefore defined may be treated with 2-hydrazinobenzoic acid (2) in aqueous media to afford intermediate phenylhydrazone (12). Intermediate phenylhydrazone can be subjected to microwave radiation to facilitate a Fischer-indole cyclization in an acidic media such as, but not limited to, formic acid to yield the substituted indeno[1,2-b] indole (13). Standard procedures may then be utilized to introduce R4 when R4 is not a hydrogen atom to give carboxylic acid 14. 
The carboxylic acid moiety of substituted benzo[4,5]furo[3,2-b]indole 4, carboxylic acid 5, indeno[1,2-b]indole 9, carboxylic acid 10, substituted indeno[1,2-b]indole 13 and carboxylic acid 14 may be elaborated into other groups represented by Z in Formulae (I) and (II). For example, treatment with an alkaline base or alkaline earth base will result in formation of the corresponding carboxylate salts. Treatment with an alcohol (R7OH, where R7 is as described above) in the presence of acid will result in formation of an ester. Esters may also be formed by other methods known to those versed in the art.
Reduction of the ester with an appropriate reducing agent such as diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride will afford the corresponding alcohol or aldehyde. If only the alcohol is formed, it may be oxidized to the aldehyde with an appropriate mild oxidant such as pyridinium chlorochromate of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, or tetrapropoylammonium perruthenate in acetonitrile in the presence of 4 xc3x85 sieves.
The carboxylic acid moiety may also be converted to the corresponding amide by treatment with an amine xe2x80x94(NHR8R9, where R8 and R9 are described above) in the presence of an activating agent such as 2-dimethylaminoisopropyl chloride hydrochloride/4-dimethylaminopyridine, or diethyl azodicarboxylate/triphenyl phosphine. Alternatively, the carboxylic acid may be converted to the corresponding acid chloride derivative using an appropriate agent such as thionyl chloride or oxalyl chloride. Treatment with the appropriate amine xe2x80x94(NHR8R9, where R8 and R9 are as described above) in the presence of an external base would then afford the desired amide.
In a similar manner, the corresponding hydroxamic acid may be prepared by treatment of the acid chloride derivative with an appropriately substituted hydroxylamine (NHR8OH, where R8 is as described above). Treatment of the carboxylic acid with urea in the presence of strong acid will provide the corresponding nitrile (Z is CN). The nitrile may be converted to a tetrazole via a cyclization reaction with sodium azide.
Alkylation of the carboxylic acid with Cl(R10)COC(O)R11 using the conditions as described by Kim, K. S. et al. J. Med. Chem. 1993, 36, 2335 in the presence of an appropriate base or Ag2O in a solvent such as tetrahydrofuran or dichloromethane; or with ClCH2C(O)N(R12R13) using the conditions as reported by Bundgaard, H. Int. J. Pharm. 1989, 55, 91 in the presence of sodium iodide/N,N-dimethylformamide and an appropriate base, will afford the bioequivalent prodrug analogs.
The compounds of Formulae (I) and (II) and their pharmaceutically acceptable salts relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence), or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma, and hair loss. Furthermore, the compounds of Formulae (I) and (II) are active as potassium channel activators which render them useful for treatment of peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders.
Compounds of the present invention potently relax smooth muscle in standard pharmacological tests. The compounds of this invention exert their smooth muscle relaxatory activity via activation of potassium channels. In addition, the compounds of the present invention are unique in that they posses intrinsic selectivity for bladder tissue over vascular tissue as demonstrated by bladder/aorta IC50 ratios (Table 1).
The present invention also provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may also be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and xcex2-blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of Formula (I) and (II) are of particular use in the induction of smooth muscle relaxation.
The present invention further provides a method of treating smooth muscle disorders in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.